Introduction: Unclassifiable Interstitial Lung Disease (uILD) is a complex entity that requires integrated evaluation across pulmonology, radiology and histology. Diagnostic pathways and management remain non-uniform, and distinct outcomes have been reported.
Objectives: To assess the diagnostic approach, the role of biopsy techniques, and their association with prognosis in patients with uILD.
Materials and Methods: We conducted a multicenter retrospective cohort study including patients with uILD diagnosed at the multidisciplinary meetings between January 2015 and January 2026. Demographic, clinical characteristics, diagnostic work-up, including biopsy procedures, and survival outcomes were collected.
Results: Seventy-five patients were classified as uILD at multidisciplinary discussion, with male predominance. Mean age at diagnosis was 68.5±9.3 years and the median time from initial evaluation to a definitive diagnosis was 4[1;9] months.
In 53.3% (n=40) of patients, a histological sample was obtained through at least one biopsy technique, most commonly due to clinical–radiological discordance (72.5%), particularly when imaging suggested alternative diagnoses such as hypersensitivity pneumonitis or idiopathic pulmonary fibrosis. Transbronchial lung cryobiopsy was the most frequently used method (45.3%), followed by surgical lung biopsy (n=5). Regardless of the technique, pathological results were unclassifiable in the majority of cases (n=27; 64.3%), with a usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia (NSIP) pattern identified in only four patients.
No significant difference in survival was observed between patients who underwent lung biopsy and those who did not.
Conclusions: In this cohort of patients with uILD diagnosed through multidisciplinary discussion, histological assessment was performed in only a subset and frequently yielded unclassifiable results. These findings underscore the central role of multidisciplinary evaluation in this setting and highlight the value of current biopsy approaches in excluding other common differential diagnoses. Further studies are needed to clarify potential histopathological findings with prognostic relevance in this population.